Blackmun graduated in mathematics from Harvard University in 1929 and received his law degree from that institution in 1932. He joined a Minneapolis, Minnesota, law firm in 1934, and while advancing to general partner in the firm he also taught at the St. Paul College of Law (1935–41). In 1950 he became resident counsel for the Mayo Clinic in Rochester, Minnesota, and held this post until 1959, when he was appointed a judge of the U.S. Court of Appeals by President Dwight D. Eisenhower (Eisenhower, Dwight D.).

In 1970, after two of his previous nominees had been rejected by the Senate as unqualified, President Richard M. Nixon (Nixon, Richard M.) named Blackmun to the Supreme Court (Supreme Court of the United States). Blackmun was unanimously confirmed by the Senate and took his seat in June 1970. On the court he joined his close friend from childhood, Chief Justice Warren E. Burger (Burger, Warren E.). He was expected to vote as a conservative constitutionalist, and for the first few years of his judgeship he did just that, voting in line with court conservatives.

In 1973, however, he wrote the court's majority decision in Roe (Roe v. Wade) v. Wade, the landmark case in which a woman's right to terminate a pregnancy was guaranteed under the constitutional right to privacy. While the decision cannot be construed as legally conservative, in that the case made law in an area ( abortion rights) in which the Supreme Court had rarely before issued an opinion, it can be seen as politically conservative, in that it followed from Blackmun's deeply held belief in a citizen's right to privacy without governmental interference. Although there were six justices who joined with Blackmun in the majority opinion of Roe v. Wade, Blackmun was linked with and characterized by that decision for the rest of his career.

At times, Blackmun's dissenting opinions became just as important to the legal debate on individual liberty as were his concurring opinions. For instance, on the issue of gay rights (gay rights movement) Blackmun wrote an eloquent dissent from the majority decision in Bowers v. Hardwick in 1986, in which the court decided 5–4 to reject a right-to-privacy claim made by a gay man convicted under a state sodomy law. Blackmun's dissent eventually framed the legal debate around this issue. Blackmun frequently argued that U.S. citizens have a fundamental right “to be left alone” by their government, and while Blackmun's opinions rarely expanded the legal rights of those accused of criminal acts, they did provide an increased right to privacy on the part of ordinary citizens. Blackmun was also a staunch supporter of the First Amendment (Constitution of the United States), of the strong separation of church and state (church and state), and of affirmative action. At the end of his legal career, Blackmun shifted his opinion on the constitutionality of the death penalty (capital punishment) because of his growing belief that the death penalty was applied in an inherently random and arbitrary fashion. He retired from the bench in 1994.